Genome-wide DNA methylation analyses in lung adenocarcinomas: Association with EGFR, KRAS and TP53 mutation status, gene expression and prognosis.
Genome-wide DNA methylation analyses in lung adenocarcinomas: Association with EGFR, KRAS and TP53 mutation status, gene expression and prognosis.
复制标题
DOI：
10.1016/j.molonc.2015.10.021
复制
发表时间：
2016-02
影响因子：
6.6
通讯作者：
Helland Å
中科院分区：
文献类型：
--
作者：
Bjaanæs MM;Fleischer T;Halvorsen AR;Daunay A;Busato F;Solberg S;Jørgensen L;Kure E;Edvardsen H;Børresen-Dale AL;Brustugun OT;Tost J;Kristensen V;Helland Å
背景：DNA甲基化改变是肿瘤发生的早期事件，在癌细胞基因表达调控中起重要作用。肺癌患者的预后一般较差，需要更深入地了解肺腺癌肿瘤的表观遗传学及其预后意义。 结果如下：我们使用Illumina Infinium 450 K阵列测定了164份新鲜冷冻肺腺癌样本和19份匹配的正常肺组织样本的全基因组DNA甲基化谱。在肺腺癌组织中发现了大量差异甲基化的CpG，在EGFR-、KRAS-或TP 53基因突变的肿瘤中以及根据患者的吸烟状况观察到特异性甲基化谱。甲基化水平与基因表达相关，且存在正相关和负相关。肿瘤样品的甲基化谱鉴定了具有不同预后的肿瘤亚型，包括一种富含TP 53突变肿瘤的亚型。建立了基于33个CpG的甲基化水平的预后指数，并且在使用来自癌症基因组图谱项目的肺腺癌患者的独立队列的单变量分析中与预后显著相关。HOX B和HOX C基因簇中的CpG在预后标志中表示。 结论：甲基化差异反映了肺腺癌病因学的重要生物学特征，并影响预后。广泛的DNA甲基化变化与免疫信号有关。EGFR突变肿瘤中与致癌途径相关的DNA甲基化。DNA甲基化与mRNA表达呈正、负相关。具有预后信息的DNA甲基化特征。
Background: DNA methylation alterations are early events in tumorigenesis and important in the regulation of gene expression in cancer cells. Lung cancer patients have in general a poor prognosis, and a deeper insight into the epigenetic landscape in lung adenocarcinoma tumors and its prognostic implications is needed. Results: We determined whole‐genome DNA methylation profiles of 164 fresh frozen lung adenocarcinoma samples and 19 samples of matched normal lung tissue using the Illumina Infinium 450K array. A large number of differentially methylated CpGs in lung adenocarcinoma tissue were identified, and specific methylation profiles were observed in tumors with mutations in the EGFR‐, KRAS‐ or TP53 genes and according to the patients' smoking status. The methylation levels were correlated with gene expression and both positive and negative correlations were seen. Methylation profiles of the tumor samples identified subtypes of tumors with distinct prognosis, including one subtype enriched for TP53 mutant tumors. A prognostic index based on the methylation levels of 33 CpGs was established, and was significantly associated with prognosis in the univariate analysis using an independent cohort of lung adenocarcinoma patients from The Cancer Genome Atlas project. CpGs in the HOX B and HOX C gene clusters were represented in the prognostic signature. Conclusions: Methylation differences mirror biologically important features in the etiology of lung adenocarcinomas and influence prognosis. Extensive DNA methylation changes linked to immune signaling. DNA methylation in EGFR‐mutated tumors associated with oncogenic pathways. DNA methylation with both positive and negative correlation with mRNA expression. DNA methylation signature with prognostic information.
登录
查看更多内容
影响因子：
11.2
作者：
Lin, Ruo-Kai;Wu, Chiu-Yi;Wang, Yi-Ching
通讯作者：
Wang, Yi-Ching
影响因子：
56.9
作者：
Gaudet, F;Hodgson, JG;Jaenisch, R
通讯作者：
Jaenisch, R
影响因子：
4.7
作者：
Heller, Gerwin;Babinsky, Valerie N.;Zoechbauer-Mueller, Sabine
通讯作者：
Zoechbauer-Mueller, Sabine
影响因子：
8.8
作者：
Kawabata S;Mercado-Matos JR;Hollander MC;Donahue D;Wilson W 3rd;Regales L;Butaney M;Pao W;Wong KK;Jänne PA;Dennis PA
通讯作者：
Dennis PA
影响因子：
3.9
作者：
Carvalho RH;Haberle V;Hou J;van Gent T;Thongjuea S;van Ijcken W;Kockx C;Brouwer R;Rijkers E;Sieuwerts A;Foekens J;van Vroonhoven M;Aerts J;Grosveld F;Lenhard B;Philipsen S
通讯作者：
Philipsen S